Periodic Reporting for period 2 - ANTIBODYPAIN (Autoantibodies and chronic pain - Unraveling new mechanisms contributing to pain in rheumatic disease)
Período documentado: 2022-04-01 hasta 2023-09-30
Chronic pain radically restricts patients` lives and has immense socio-economic sequelae when considering the costs for diagnostics and treatment attempts amplified by loss of working capacity. Pain remains one of the most challenging symptoms in rheumatic diseases such as rheumatoid arthritis (RA) and fibromyalgia (FM), yet its underlying mechanisms remain largely unclear, especially in the case of FM. For a considerable time, FM has been unjustly sidelined as a mere functional, psychosomatic, or even nonexistent condition. This misperception has inflicted a significant and persistent burden on FM patients, compounding their symptoms. FM causes chronic pain and fatigue in 2-5% of the population, particularly among women, and yet, there are no objective diagnostic criteria and the efficacy of current treatments is notably limited. Consequently, it is imperative to delve into the underlying mechanisms of pain in FM to change this scenario. Here we have focused on the role of antibodies (IgG) isolated from individuals with FM in pain, and are undertaking parallel experiments with antibodies from individuals with RA. The overall objective of this project is to investigate 1) how IgG from individuals with FM and RA induce pain by exploring changes in behavior, and cell interactions, 2) search for pain-related autoantigens in FM, and 3) map FM and RA IgG-induced maladaptive changes in sensory neurons that mediate hyperexcitability pain chronicity.
Our investigations have been centered on the influence of antibodies (IgG) from FM and RA patients on pain-like behaviors and pain mechanisms after transfer to mice. We have uncovered that FM antibodies heighten sensitivity to mechanical and cold stimulation and reduce grip strength and amount of movement in mice. Furthermore, the transfer of antibodies to mice causes a reduction in nerve fiber density in the skin, which is also detected in about 50% of patients with FM. The antibodies accumulate in the dorsal root ganglia, a tissue where the cell bodies of sensory neurons are located, and there the IgG binds to satellite glial cells which closely enwrap the neuronal cell bodies. The IgG also binds to some extent also to macrophages, a cell type that belongs to our immune system. FM IgG displayed a similar binding pattern in human dorsal root ganglia suggesting a translatability of our findings between mouse and man. Another important observation is that the levels of antibodies binding to satellite glial cells correlated with the degree of pain reported by FM patients. Taken together, these findings suggest that there is an autoimmune component underpinning pain in FM and that complex multi-cell interactions in the dorsal root ganglia contribute to the pain pathophysiology.
The RA-associated autoantibodies that have been examined to date also increased pain sensitivity in mice without causing evident tissue inflammation. Interestingly, after injection to mice, RA IgG was found to exert their pronociceptive actions both in local structures in the joint and in the dorsal root ganglia where they exerted actions on satellite glial cells and macrophages, partially dependent on the presence of Fc-gamma receptors. This indicates that the formation of immune complex and activation of Fc-gamma receptors on either immune cells or pain fibers also contribute to the development of pain chronicity.
The RA-associated autoantibodies that have been examined to date also increased pain sensitivity in mice without causing evident tissue inflammation. Interestingly, after injection to mice, RA IgG was found to exert their pronociceptive actions both in local structures in the joint and in the dorsal root ganglia where they exerted actions on satellite glial cells and macrophages, partially dependent on the presence of Fc-gamma receptors. This indicates that the formation of immune complex and activation of Fc-gamma receptors on either immune cells or pain fibers also contribute to the development of pain chronicity.
Prior to our investigations, research centered on the central nervous system illuminated the critical role of central sensitization and altered pain signal modulation in the pathophysiology of fibromyalgia. Simultaneously, studies focused on the peripheral nervous system highlighted the role of small nerve fiber damage in the skin in FM pain. Our groundbreaking discovery of pathogenic autoantibodies in FM represents a significant stride toward advancement in understanding of processes underlying pain in FM. We anticipate that our work will serve as a foundation and have the potential to reshape the perspectives and approaches of scientists and medical professionals worldwide in understanding and managing FM.
Medical illnesses often struggle for credibility - until the underlying pathogenesis is identified and better understood. We hold optimism that this trajectory will extend to fibromyalgia as well. Validating a peripheral pathology, identifying FM-specific autoantigens, and pinpointing associated autoantibodies, even within specific FM subgroups, will mark a breakthrough for devising diagnostic tools, innovating treatment strategies, and deepening our insights into the biological disturbances of the disease. A pivotal aspect of our revelation is that IgG can trigger heightened sensitivity without prompting overt tissue inflammation. This observation raises the intriguing possibility that this "silent autoimmunity" may extend its relevance beyond FM and RA to encompass other chronic pain conditions associated with either established or yet undiscovered autoimmunity.
Medical illnesses often struggle for credibility - until the underlying pathogenesis is identified and better understood. We hold optimism that this trajectory will extend to fibromyalgia as well. Validating a peripheral pathology, identifying FM-specific autoantigens, and pinpointing associated autoantibodies, even within specific FM subgroups, will mark a breakthrough for devising diagnostic tools, innovating treatment strategies, and deepening our insights into the biological disturbances of the disease. A pivotal aspect of our revelation is that IgG can trigger heightened sensitivity without prompting overt tissue inflammation. This observation raises the intriguing possibility that this "silent autoimmunity" may extend its relevance beyond FM and RA to encompass other chronic pain conditions associated with either established or yet undiscovered autoimmunity.